Herpesviruses have been suggested as co-factorsfor progression of fibrotic lung disease. Lytic infection with gammaherpesviruses-68 (YHV68) can exacerbate established fluorescein isothiocyanate (FITC)- induced lung fibrosis in mice. This is associated with increased viral replication, chemokine production and recruitment of fibrocytes. TLR9 is important in innate defense against herpesvirus. TLR9-deficient mice had more robust exacerbation of FITC-fibrosis with yHV68 infection compared to wild-type mice, suggesting that TLR9 is protective against viral-induced exacerbations of fibrosis. Chimeric mice with TLR9 on structural cells such as alveolar epithelial cells (AECs), but absent on hematopoietic cells were protected fromyHV68- induced exacerbation of fibrosis when compared to TLR9-/- mice. Thus, TLR9 signaling in structural cells limits the profibrotic effects of herpesvirus. Infection of wild-type AECs with yHV68 results in viral replication, release of active transforming growth factor (TGF)(31, and tumor necrosis factor (TNF)a. Infection of TLR9-/- AECs results in somewhat enhanced viral replication, but significantly enhanced TNFa production, increased endoplasmic reticulum stress and abundant apoptosis when compared to infection of wild-type AECs. It is likely that enhanced apoptosis of AECs could result in the more severe exacerbation of FITC-fibrosis following infection with yHV68 noted in TLR9-/- mice. Thus, I hypothesize that TLR9 activation by gammaherpesviruses in AECs serves to limit profibrotic apoptosis. These studies will explore potential mechanisms of viral exacerbation of fibrosis using both animal modeling and ex vivo culture of human and murine AECs. Aim 1: To determine the role of TLR9 in regulating Ivtic and latent infection with vHV68 and to determine whether the vHV68-associated fibrotic alterations are acute, persistent or progressive: Aim 2: To explore the role of TLR9 in regulating apoptosis during vHV68 infection in murine AECs: Aim 3: To explore the role of TLR9 signaling in regulating apoptosis during Epstein Barr virus (EBV) infection of human AECs. These studies will be carried out in an outstanding research environment under the guidance of dedicated senior personnel according to a carefully considered career development plan. The overall goal is to provide rich training opportunities in both basic and translational science which will allow me to achieve my long-term career goal of becoming an independent academic physician-scientist. RELEVANCE (See instructions): Idiopathic pulmonary fibrosis is a fatal fibrotic lung disease with no known cause or treatment. Patients often die from acute exacerbations of this disease. This project will provide mechanistic insight into the potential role that viral infections may play in causing exacerbations of lung fibrosis.